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Background & Aim: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined., Methods: We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant., Results: The KLB rs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression., Conclusion: In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes., Lay Summary: Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: We examined the diagnostic performance of plasma N-terminal propeptide of type III procollagen (PIIINP) levels, aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for predicting non-alcoholic steatohepatitis (NASH) and liver fibrosis stage in children/adolescents with non-alcoholic fatty liver disease (NAFLD)., Methods: We enrolled 204 children/adolescents with biopsy-proven NAFLD at the "Bambino Gesù" Children's Hospital. We measured plasma PIIINP levels using a commercially available enzyme-linked immunosorbent assay kit and calculated APRI and FIB-4 scores using standard methods., Results: Children with NASH had higher plasma PIIINP levels, APRI and FIB-4 scores compared with those without NASH (all P < .001). However, PIIINP levels had much better diagnostic performance and accuracy than APRI and FIB-4 scores for predicting liver fibrosis stage. PIIINP levels correlated with the total NAFLD activity score (NAS) and its constituent components (P < .0001). The risk of either NASH or F ≥ 2 fibrosis progressively increased with increasing PIIINP levels (P < .0001), independent of age, gender, adiposity measures, insulin resistance, NAS score and the patatin-like phospholipase domain-containing protein-3 rs738409 polymorphism. For every 3.6 ng/mL increase in PIIINP levels, the likelihood of having F ≥ 2 fibrosis increased by ~14-fold (adjusted-odds ratio 14.1, 95% CI 5.50-35.8, P < .0001) after adjustment for the aforementioned risk factors. The area under the receiver operating characteristics curve was 0.921 (95% CI 0.87-0.97) for F ≥ 2 fibrosis, and 0.993 (95% CI 0.98-1.0) for F3 fibrosis respectively., Conclusions: Unlike APRI and FIB-4 scores, plasma PIIINP levels are a promising, non-invasive biomarker for diagnosing liver fibrosis stage in children/adolescents with biopsy-proven NAFLD., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis., Methods: We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also collected data on demographic features, metabolic comorbidities, and genetic factors, and performed logistic regression analyses. Findings were validated using data from 118 consecutive patients with NAFLD who underwent sequential liver biopsies at tertiary referral centers in Italy., Results: In the cross-sectional cohort, 132 of 389 patients (33.9%) with significant fibrosis had no NASH and 39 patients (10.0%) had no inflammation. The dissociation between NASH and fibrosis was significantly greater in patients with severe obesity (P < .005). Steatosis, ballooning, and lobular inflammation each were associated independently with significant fibrosis (P < .001); age, adiposity, fasting hyperglycemia, and the PNPLA3 I148M variant also were associated with fibrosis. In patients without, but not in those with NASH, significant fibrosis was associated with steatosis grade and the PNPLA3 I148M variant. In patients without NASH, age, fasting hyperglycemia, ballooning, and inflammation were associated with fibrosis. In the validation cohort, 16 of 47 patients (34.0%) with clinically significant fibrosis did not have NASH at baseline. In patients with fibrosis without baseline NASH, worsening of fibrosis (based on later biopsies) was associated with fasting hyperglycemia and more severe steatosis (P = .016)., Conclusions: In an analysis of biopsy specimens collected from patients with NAFLD at a single time point, one third of patients with significant fibrosis did not have NASH. We validated this finding in a separate cohort. In patients without NASH, fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and the PNPLA3 I148M variant identified those at risk of significant fibrosis., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Hemoglobin (Hb) and red blood cell distribution width (RDW) have been reported to be a risk marker of metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). No study exists on pediatric populations. We aimed to determine the association between hematological parameters, and the severity of disease in children with biopsy-proven NAFLD., Methods: A total of 117 children (85 boys, mean age 12 years) with ultrasound evidence of NAFLD undergoing liver biopsy for diagnosis of nonalcoholic steatohepatitis (NASH), were prospectively enrolled between January 2011 and May 2013 in the setting of a tertiary care center. Children were screened for routine hematological and metabolic parameters, and causes of liver steatosis other than nonalcoholic were excluded, before liver biopsy was performed., Results: A total of 41 NAFLD (boys 29, mean age 11.2 years) and 76 NASH (boys 56, mean age 12.8 years) children were studied. Alanine transaminase levels were significantly higher in NASH group compared with NAFLD group (P = 0.05), and homeostatic model assessment of insulin resistance and triglycerides levels (P = 0.03 and 0.02, respectively). Regarding hematological components: red cell count, Hb, hematocrit, and RDW values were all significantly higher in NASH group compared with NAFLD group (P < 0.05 for each parameter)., Conclusions: Children with NASH were more likely to have high levels of RDW compared to those with steatosis only. Moreover, NASH was associated with higher red cell count, Hb, and hematocrit. If confirmed in future follow-up studies, hematological parameters may be introduced in algorithms for NASH risk prediction.

Purpose To evaluate the diagnostic accuracy of shear-wave elastography (SWE) in identifying different degrees of fibrosis in a cohort of consecutive children and adolescents with nonalcoholic steatohepatitis (NASH). Materials and Methods Consecutive pediatric patients scheduled to undergo liver biopsy were studied with an ultrasonography-based SWE system. Elastography was performed in 68 of 69 patients with biopsy-proved NASH (37 boys and 31 girls; mean age, 12.6 years ± 2.48; age range, 8-17 years). The correlations among laboratory findings, liver stiffness, and fibrosis score were analyzed, and the area under the receiver operating characteristic curve (AUC) was used to assess the presence of any fibrosis (score ≥F1) or significant fibrosis (score ≥F2). Findings from histologic examination were used as the standard of reference. Results SWE showed a very high correlation with liver fibrosis (P < .001) at univariate and multivariate analyses. The AUCs for the association of any and significant fibrosis were 0.92 (95% confidence interval [CI]: 0.86, 0.98) and 0.97 (95% CI: 0.95, 0.99), respectively. The intraclass correlation coefficient for absolute agreement was 0.95 (95% CI: 0.90, 0.97). Conclusion SWE is an accurate and reproducible noninvasive technique that efficiently depicts the presence of significant liver fibrosis and, less accurately, mild liver fibrosis in pediatric patients with nonalcoholic fatty liver disease. Larger clinical prospective studies are warranted to confirm SWE accuracy and establish threshold values for fibrosis grading in comparison or in combination with other noninvasive methods. © RSNA, 2016.

Objective: To determine whether bariatric surgery is effective for the treatment of nonalcoholic steatohepatitis (NASH) in adolescence, we compared the efficacy of laparoscopic sleeve gastrectomy (LSG) with that of lifestyle intervention (nonsurgical weight loss [NSWL]) for NASH reversal in obese adolescents., Study Design: Obese (body mass index ≥ 35 kg/m 2 ) adolescents (13-17 years of age) with biopsy-proven NAFLD underwent LSG, lifestyle intervention plus intragastric weight loss devices (IGWLD), or only NSWL. At baseline and 1 year after treatment, patients underwent clinical and psychosocial evaluation, blood tests, liver biopsy, polysomnography, and 24-hour ambulatory blood pressure estimation., Results: Twenty patients (21%) underwent LSG, 20 (21%) underwent IGWLD, and 53 (58%) received lifestyle intervention alone (NSWL). One year after treatment, patients who underwent LSG lost 21.5% of their baseline body weight, whereas patients who underwent IGWLD lost 3.4%, and patients who underwent NSWL increase 1.7%. In patients who underwent LSG, NASH reverted completely in all patients and hepatic fibrosis stage 2 disappeared in 18 patients (90%). After IGWLD, NASH reverted in 6 patients (24%) and fibrosis in 7 (37%). Patients who received the NSWL intervention did not improve significantly. Hypertension resolved in all patients who underwent LSG with preoperative hypertension (12/12) versus 50% (4/8) of the patients who underwent IGWLD (P = .02). The cohort-specific changes in impaired glucose metabolism were similar: 100% (9/9) of affected patients who underwent LSG versus 50% (1/2) of patients who underwent IGWLD (P = .02). LSG was also more affective in resolving dyslipidemia (55% [7/12] vs 26% [10/19]; P = .05) and sleep apnea (78% [2/9] vs 30% [11/20]; P = .001)., Conclusion: LSG was more effective than lifestyle intervention, even when combined with intragastric devices, for reducing NASH and liver fibrosis in obese adolescents after 1 year of treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Within the spectrum of nonalcoholic fatty liver disease (NAFLD), recent evidence suggests that adult patients with nonalcoholic steatohepatitis (NASH) have significantly lower blood lysosomal acid lipase (LAL) activity than those with steatosis. This has not been studied in pediatric patients with NAFLD., Aim: Investigate blood LAL activity in pediatric patients with NAFLD and assess its correlation with histological severity., Methods: We collected data on consecutive children with biopsy-proven NAFLD including demographics, anthropometrics, and routine laboratory tests. The histological features were graded according to the NAFLD activity scoring proposed by Kleiner et al. Blood LAL activity was measured prospectively using Lalistat 2., Results: A total of 168 children were included for analysis. Mean age was 12.6±8.5 years, 60.1% were males and 52.4% had NASH. Children with significant fibrosis (stage 2-3, n=64) had a significantly lower LAL activity compared to those with mild fibrosis (stage 0-1, n=104). There was no significant difference in LAL activity between children with NASH compared to those without NASH., Conclusion: Reduced blood LAL activity correlates with severity of liver fibrosis in children with NAFLD indicating a potential role of reduced LAL activity in the pathogenesis of NAFLD-induced fibrosis., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the obesity epidemic and affects approximately 10% of children in the US. The presence of hepatic fibrosis may be the most important factor in determining the prognosis of NAFLD. Noninvasive methods to identify the presence of fibrosis in children with NAFLD are greatly needed. Hepatocyte apoptosis activates hepatic stellate cells and plays a central role in fibrosis progression in NAFLD. The aim of the present study was to evaluate the use of plasma cytokeratin-18 (CK18) fragment levels, a marker of hepatocyte apoptosis, as a noninvasive biomarker in detecting liver fibrosis in pediatric NAFLD., Methods: Consecutive children with biopsy-proven NAFLD were included and blood samples and anthropometric measurements were collected at the time of the biopsy. NAFLD activity score was calculated (0-8) and fibrosis stage was scored (0-4). We measured plasma CK18 levels using the M30-Apoptosense enzyme-linked immunosorbent assay kit., Results: A total of 201 subjects were enrolled in the study. The mean age was 10.7 ± 2.5 years, and 37 % were boys. Sixty-eight percent of the patients had any fibrosis, with 56% having F1, 6% having F2, and 6 % having F3. CK18 levels were found to be significantly higher in subjects with any fibrosis compared with those without fibrosis (304.6 ± 124.8 vs 210.4 ± 70.9, P < 0.001). CK18 level revealed good accuracy for prediction of any fibrosis (F1-F3) with AUROC of 0.75. Multivariate logistic regression was performed to assess whether CK18 in combination with another clinical factor could improve accuracy of prediction of fibrosis. Together, CK18 with waist circumference percentile generated an area under the receiver operating characteristics curve of 0.842 for prediction of any fibrosis., Conclusions: CK18 is a promising noninvasive biomarker for fibrosis in NAFLD in children. A fibrosis prediction model that includes CK18 and waist circumference percentile should be validated in other populations.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD., Methods: We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity., Results: The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function., Conclusions: We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Glucose derangement has been reported to increase oxidative stress, one of the most important factors underlying the progression of hepatic fibrosis in adults with nonalcoholic fatty liver disease (NAFLD). To date, careful evaluation of the glucose profile in pediatric NAFLD has not been performed., Methods: A total of 30 severely obese children (15 males; mean age 12.87 ± 2.19 years) with biopsy-proven NAFLD were enrolled in this study from September to December 2013. All patients underwent anthropometric and laboratory evaluation, including the oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM)., Results: Our study reveals some differences between OGTT and CGM in detecting NAFLD children with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). OGTT showed 2 (6.67%) patients with IFG and 1 (3.34%) with IGT, while CGM showed 5 (16.67%) patients with IFG and 6 (20%) with IGT. The daily blood glucose profile positively correlated with the baseline blood glucose (r = 0.39, p = 0.04) and the homeostatic model assessment (r = 0.56, p = 0.05). A positive correlation between hyperglycemia and liver fibrosis was found (r = 0.65, p < 0.05). Mean glucose values (F3-F4 group: 163.2 ± 35.92 mg/dl vs. F1 group: 136.58 ± 46.83 mg/dl and F2 group: 154.12 ± 22.51 mg/dl) and the difference between the minimum and maximum blood glucose levels (F3-F4 group: 110.21 ± 25.26 mg/dl vs. F1 group: 91.67 ± 15.97 mg/dl and F2 group: 92 ± 15.48 mg/dl) were significantly (p < 0.05) higher in the F3-F4 group compared to the F1 and F2 groups., Conclusion: Glucose profile derangement as detected by CGM is associated with the severity of hepatic fibrosis in children with NAFLD., (© 2015 S. Karger AG, Basel.)

Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH).We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH.In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH.

Objective: Because the prevalence of obesity in children is increasing, the frequency of pediatric nonalcoholic fatty liver disease (NAFLD) is growing. A reliable noninvasive biomarker for monitoring progression of liver fibrosis would be useful. In cirrhotic persons serum bile acid (BA) levels are significantly elevated. We hypothesized that BA levels and composition in pediatric NAFLD vary depending on the stage of fibrosis., Methods: Children with NAFLD were compared with controls and classified by stages of fibrosis (NAFLD-F0, n = 27; NAFLD-F≥1, n = 65) based on liver-biopsy findings. Fasted metabolic and cholestasis status was assessed by several blood tests. BA profiles were measured by tandem mass spectrometry and compared with healthy controls (n = 105)., Results: Compared with controls, all of the NAFLD patients were overweight and showed significantly elevated glucose, insulin, aspartate transaminase, and alanine transaminase levels. Total serum BAs were lower in nonfibrotic NAFLD children than in a control cohort (1.73 vs 3.6 μmol/L) because low glycine-conjugated BA levels were incompletely compensated by increases in taurine-conjugated or unconjugated BA. In patients with fibrotic NAFLD, BA levels were lower than in controls (2.45 vs 3.6 μmol/L) but higher than in nonfibrotic patients (2.45 vs 1.73 μmol/L), and the BA pattern resembled that of healthy controls. Fibroblast growth factor 19 levels were significantly lower in both NAFLD groups than in controls (P ≤ 0.001) and were positively correlated with ursodeoxycholic acid levels., Conclusions: Our data indicate that serum BA levels decrease in early NAFLD and increase during progression to fibrosis. Given that BA levels are increased in cirrhotic adults, we postulate a continuous rise as NAFLD advances. BA may have a value as a noninvasive biomarker in pediatric NAFLD progression.

Background: Noninvasive hepatic fibrosis scores that predict the presence of advanced fibrosis have been developed and validated in adult patients with NAFLD. The aims of our study were to assess the utility of commonly used adult fibrosis scores in pediatric NAFLD and to develop a pediatric specific fibrosis score that can predict advanced fibrosis., Methods: Consecutive children with biopsy-proven NAFLD were included. Fibrosis was determined by an experienced pathologist (F0-4). Advanced fibrosis was defined as fibrosis stage ≥ 3. The following adult fibrosis scores were calculated for each child: AST/ALT ratio, AST/platelet ratio index (APRI), NAFLD fibrosis score (NFS), and FIB-4 Index. Multivariable logistic regression analysis was performed to build a new pediatric model for predicting advanced fibrosis., Results: Our cohort consisted of 242 children with a mean age of 12.4 ± 3.1 years and 63% were female. 36 (15%) subjects had advanced fibrosis. APRI and FIB-4 were higher in patients with advanced fibrosis compared to those with fibrosis stage 0-2; however, AST/ALT ratio and NFS were not different between the two groups. We used our data to develop a new model to predict advanced fibrosis which included: ALT, alkaline phosphatase, platelet counts and GGT. The multivariable logistic regression model (z) was defined as follows: z = 1.1+(0.34*sqrt(ALT))+(0.002*alkaline phosphatase) - (1.1*log(platelets) - (0.02*GGT). This value was then converted into a probability distribution (p) with a value between 0 to 100 by the following formula: p = 100 × exp(z)/[1+exp(z)]. The AUCROC for this model was 0.74 (95% CI: 0.66, 0.82). This was found to be significantly better than APRI, NAFLD Fibrosis Score and FIB-4 Index., Conclusion: Noninvasive hepatic fibrosis scores developed in adults had poor performance in diagnosing advanced fibrosis in children with NAFLD. We developed a new pediatric NAFLD fibrosis score with improved performance characteristics.

Non-alcoholic fatty liver disease (NAFLD) affects 3-12% of the general pediatric population. HMGB1 protein is presently considered a potent inflammatory mediator in several liver diseases, even if its role in NAFLD is still unknown in clinical studies. Here we investigated the relationships between circulating HMGB1, TGF-β and MCP-1 and liver damage in pediatric NAFLD. HMGB1, TGF-β and MCP-1 plasma levels were measured in 110 obese children with biopsy-proven NAFLD and 40 age-matched obese controls. HMGB1, TGF-β and MCP-1, ALT, AST and cholesterol plasma levels were significantly higher in NAFLD than in control children. A significant association between increased levels of HMGB1, TGF-β and MCP-1 and high degrees of fibrosis was found. In this study, we showed for the first time that circulating levels of HMGB1 were raised in children with NAFLD and strongly correlated with fibrosis and systemic inflammation.

Objective: Obesity in childhood is associated with an inflammatory state in adipose tissue and liver, which elevates risk for diabetes and liver disease. No prior study has examined associations between pathologies occurring in adipose tissue and liver to identify elements of tissue damage associated with type 2 diabetes risk. This study sought to determine whether inflammation and fibrosis in abdominal subcutaneous adipose tissue (SAT) in obese/overweight children (BMI-z 2.3 ± 0.76) was related to the extent of observed liver disease or type 2 diabetes risk., Methods: Biopsy samples of abdominal (SAT) and liver were simultaneously collected from 33 Italian children (mean BMI 28.1 ± 5.1 kg/m(2) and mean age 11.6 ± 2.2 years) with confirmed NAFLD. Histology and immunohistochemistry were conducted on biopsies to assess inflammation and fibrosis in adipose tissue and fibrosis and inflammation in liver., Results: Presence vs. absence of crown-like structures (CLS) in SAT was significantly related to liver fibrosis scores (1.7 ± 0.7 vs. 1.2 ± 0.7, P = 0.04) independent of BMI. SAT fibrosis was significantly correlated with a lower disposition index (r = -0.48, P = 0.006). No other adipose measures were associated with liver disease parameters., Conclusion: Markers of subcutaneous white adipose tissue inflammation are associated with greater extent of liver fibrosis independent of obesity and SAT fibrosis may contribute to diabetes risk through reduced insulin secretion., (Copyright © 2014 The Obesity Society.)

Non-alcoholic fatty liver disease is a multifactorial condition, ranging from simple steatosis to non-alcoholic steatohepatitis with or without fibrosis. In non-alcoholic fatty liver disease, alteration of gut microbiota and increased intestinal permeability increase exposure of the liver to gut-derived bacterial products: lipopolysaccharides and unmethylated CpG DNA. These products stimulate innate immune receptors, namely Toll-like receptors, which activate signalling pathways involved in liver inflammation and fibrogenesis. Currently, there are several studies on the involvement of lipopolysaccharide-activated Toll-like receptor 4 signalling in non-alcoholic fatty liver disease pathogenesis. There has been widespread interest in the study of the involvement of resident hepatic stellate cells and Kupffer cells activation in liver fibrogenesis upon TLR4 stimulation. Although the best evidence to support a role for gut microbiota in non-alcoholic fatty liver disease-induced fibrosis comes largely from animal models, data from human studies are accumulating and could lead to new therapeutic approaches. Therapeutic modulation of gut microflora may be an alternative strategy to develop an anti-fibrotic therapy. In this review, we discuss the relevant role of gut-liver axis in non-alcoholic liver disease-associated liver fibrosis and discuss the evidence on novel anti-fibrotic therapeutic approaches., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease from simple steatosis to steatohepatitis, to fibrosis and cirrhosis. The paediatric NAFLD fibrosis index (PNFI) and transient elastography (TE) are potential noninvasive markers for fibrosis. To prospectively evaluate the performance of PNFI and TE in assessing clinically significant fibrosis in children with biopsy-proven NAFLD., Methods: Our cohort consisted of 67 consecutive children with biopsy-proven NAFLD. The stage of fibrosis was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network. Fibrosis ≥ 2 was considered clinically significant. PNFI was calculated using age, waist circumference and triglycerides. TE was performed using the Fibroscan apparatus., Results: Ten patients had fibrosis stage 2-3 and 57 patients had stage 0-1. Both PNFI and TE values were significantly higher in patients with significant fibrosis (P < 0.05). The area under the receiver operating characteristic (ROC) curve for predicting significant fibrosis of PNFI and TE were 0.747 and 1.00 respectively (P = 0.005). The combined use of PNFI and TE could predict the presence or absence of clinically significant fibrosis in 98% of children with NAFLD., Conclusions: In children with NAFLD, the combination of PNFI and TE can be used to accurately assess the presence of clinically significant liver fibrosis. This will help to identify patients who should undergo liver biopsy because the confirmation of advanced fibrosis would lead to closer follow-up and screening for cirrhosis-related complications., (© 2012 John Wiley & Sons A/S.)

Unlabelled: Hepatic progenitor cells (HPCs) play a major role in liver repair and regeneration. We evaluated HPC involvement in pediatric nonalcoholic fatty liver disease (pNAFLD). Thirty biopsies of consecutive children and adolescents with untreated NAFLD (19 with nonalcoholic steatohepatitis [NASH] and 11 without NASH) were studied using immunohistochemistry and immunofluorescence. HPCs and HPC-expressing adipokines (e.g., adiponectin, resistin, and glucagon-like peptide 1 [GLP-1]) were counted and correlated with steatosis, inflammation, hepatocyte ballooning, fibrosis, and NAFLD activity score (NAS). The HPC compartment was expanded in pNAFLD, especially in children with NASH, and was independently associated with degree of fibrosis (r = 0.303; P = 0.033). NASH livers were also characterized by increased hepatocyte apoptosis, cell-cycle arrest, and an expanded pool of intermediate hepatocytes. Adiponectin expression in HPCs of pNAFLD patients was down-regulated with respect to the healthy liver, and this expression was inversely correlated with NAS score (r = -0.792; P < 0.001) and steatosis (r = -0.769; P < 0.001). Resistin expression in HPCs increased in pNAFLD and was related to degree of fibrosis (r = 0.432; P < 0.05). GLP-1 was overexpressed in HPCs of pNAFLD patients, and GLP-1 expression was related to degree of steatosis (r = 0.577; P < 0.05) and NAS (r = 0.594; P < 0.01)., Conclusions: HPC activation is involved in the response of the liver to oxidative stress in pNAFLD and is correlated with fibrosis and the progression toward NASH. HPCs express adiponectin, resistin, and GLP-1, which become available to resident liver cells and are strongly associated with the severity of NAFLD. These results may have important pathophysiological implications in the modulation of hepatic insulin resistance and the progression of liver injury., (Copyright © 2012 American Association for the Study of Liver Diseases.)

The prognosis and management of chronic liver diseases in children largely depend on the extent and progression of liver fibrosis, which is often the most important predictor of disease outcome, and thus influences the indication for potential therapy. Unfortunately, liver biopsy continues to be the gold standard for the staging and grading of fibrosis. Liver biopsy is an invasive and painful technique with several limitations. These limitations have led to the development of alternative noninvasive methods for the accurate assessment of fibrosis and for the maintenance of an acceptable risk/benefit ratio. In the last decades, transient elastography (TE) has received increasing consideration as a means of evaluating disease progression in paediatric chronic liver disease. TE is an accurate and reproducible methodology for identifying subjects without fibrosis or significant fibrosis, or with advanced fibrosis. In this review, we provide an outline of liver fibrosis in paediatric liver diseases, including fibrogenesis, and noninvasive techniques for the diagnosis and follow-up of fibrosis, and then focus on the characteristics of TE and on its strength in the assessment of liver fibrosis, paying particular attention to studies conducted in children.

Numerous paediatric liver diseases from different origins may be complicated by development of liver fibrosis and progression to cirrhosis. Although fibrogenesis, which represents a major driving force for the development of liver fibrosis, has common tracts whatever the aetiology, liver fibrosis has different histopathological patterns in paediatric liver disease. In these diseases management choices may depend upon the stage of liver fibrosis. Thus, the accurate estimation of histological pattern of liver fibrosis is important for the prevention of the subsequent complications. Liver biopsy has long been considered as a gold standard diagnostic method for assessing liver fibrosis. However, due to its several disadvantages, in the last decades alternative and accurate non-invasive means to estimate fibrosis are developed. In this review, we characterised the most frequent histological patterns of liver fibrosis in paediatric liver diseases. Furthermore, we describe use of liver biopsy in diagnosis and staging of liver fibrosis, list the alternative non-invasive techniques that have an emerging role in the assessment of liver fibrosis, and propose a management algorithm., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) encompasses diseases from simple steatosis, to steatohepatitis, to fibrosis, and cirrhosis. The pediatric NAFLD fibrosis index (PNFI) and the enhanced liver fibrosis (ELF) test are potential noninvasive markers for fibrosis. We prospectively evaluated the performance of PNFI and ELF in assessing fibrosis in children with biopsy-proven NAFLD., Methods: We analyzed 111 consecutive children with NAFLD. The stage of fibrosis was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network. PNFI was calculated based on age, waist circumference, and levels of triglycerides. The ELF test was used to determine levels of hyaluronic acid, the amino-terminal propeptide of type III collagen, and tissue inhibitor of metalloproteinase-1., Results: Some degree of fibrosis was detected in 68.5% of patients (62 had stage 1, 5 had stage 2, and 9 had stage 3). PNFI and ELF test values was higher among patients with fibrosis (P < .001). The area under the receiver operating characteristic (ROC) curve for predicting fibrosis using the PNFI and ELF test was 0.761 and 0.924, respectively. The best performance was obtained by combining PNFI and ELF test with (area under the receiver operating characteristic curve = 0.944). The combined results from the PNFI and ELF test predicted the presence or absence of fibrosis in 86.4% of children with NAFLD., Conclusions: In children with NAFLD, the combined results from the PNFI and ELF test can accurately assess the presence of liver fibrosis and identify patients that should be evaluated by liver biopsy., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The non-alcoholic steato-hepatitis Clinical Research Network has recently shown that portal chronic inflammation is associated with liver fibrosis in American children with non-alcoholic fatty liver disease., Aim: We tested whether the portal chronic inflammation-fibrosis association was present in a series of Italian children with non-alcoholic fatty liver disease., Methods: We re-assessed the liver biopsies of 144 consecutive Italian children with non-alcoholic fatty liver disease aged 3-18 years and followed at the "Bambino Gesù" Paediatric Hospital. Non-alcoholic fatty liver disease and portal chronic inflammation were diagnosed using the non-alcoholic steato-hepatitis Clinical Research Network criteria. Anthropometry, body composition, liver enzymes, metabolic parameters and blood pressure were measured in all children., Results: Two children had no portal chronic inflammation, 84 had mild and 58 more than mild portal chronic inflammation according to the non-alcoholic steato-hepatitis Clinical Research Network criteria. Children with no or mild portal chronic inflammation had the same clinical features of those with more than mild portal chronic inflammation except for insulin resistance, which was greater. There was no association between steatosis, lobular inflammation, ballooning, fibrosis and portal chronic inflammation., Conclusion: We were not able to confirm the existence of a clinico-pathological association between portal chronic inflammation and disease severity in a series of Italian children with non-alcoholic fatty liver disease. Some clinico-pathological correlates of paediatric non-alcoholic fatty liver disease may be population-specific., (Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents, and it may progress to liver fibrosis and cirrhosis. Liver biopsy, which is the recognized gold standard for the diagnosis of hepatic fibrosis, is invasive. Thus, there has been increasing interest in the development of noninvasive markers. Hyaluronic acid (HA) has been shown to be a good marker of liver fibrosis in adults. In the current study, we evaluated the association of HA with liver fibrosis in 100 consecutive children with biopsy-proven NAFLD. In all, 65% of the children had liver fibrosis. Using proportional-odds ordinal logistic regression, we found that values of HA ≥ 1200 ng/mL made the absence of fibrosis (F0) unlikely (7%, 95% confidence interval [CI]: 1% to 14%), whereas values of HA ≥ 2100 ng/mL made F2, F3, or F4 fibrosis likely (89%, 95% CI: 75% to 100%). Our study shows that HA is a predictor of fibrosis in children with NAFLD followed at a tertiary care center. Additional studies are needed to test whether HA can be employed to predict liver fibrosis in pediatric populations with similar and lower prevalence of liver fibrosis., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. The aim of this study was to assess the relationship between severity of liver injury and atherogenic lipid profile in a large group of children with NAFLD. A total of 118 consecutive children with biopsy-proven NAFLD were included. Patients underwent extensive metabolic profiling. The NAFLD activity and fibrosis scores showed a significant positive correlation with triglyceride/HDL, total cholesterol/HDL, and LDL/HDL ratios (p<0.05) but not with apolipoprotein B/apolipoprotein A-1 ratio (p=0.58). After adjusting for BMI, homeostatic model assessment, impaired glucose tolerance, and presence of metabolic syndrome, both the NAFLD activity score and stage of fibrosis remained independent predictors of proatherogenic lipid profile. All lipid ratios, except for apolipoprotein B/apolipoprotein A-1, were found to be markedly higher in children with nonalcoholic steatohepatitis compared with those with simple steatosis or borderline disease (p<0.05). This study shows for the first time that in children with NAFLD, the severity of liver injury is strongly associated with the presence of a more atherogenic lipid profile, having potential significant diagnostic and therapeutic implications.

Unlabelled: Inherited factors play a major role in the predisposition to nonalcoholic fatty liver disease (NAFLD), and the rs738409 C-->G polymorphism of PNPLA3/adiponutrin, encoding for the isoleucine-to-methionine substitution at residue 148 (I148M) protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P = 0.001). In Italian and United Kingdom patients, adiponutrin genotype influenced alanine aminotransferase levels and the severity of steatosis. Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule Fas ligand. In the whole series combined, adiponutrin genotype was associated with steatosis grade >1 (OR = 1.35, 95% CI = 1.04-1.76), nonalcoholic steatohepatitis (OR = 1.5, 95% CI = 1.12-2.04), and fibrosis stage >1 (OR = 1.5, 95% CI = 1.09-2.12), independent of age, body mass index, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes., Conclusion: In patients with NAFLD, adiponutrin rs738409 C-->G genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis.

Purpose of Review: This review summarizes the current state of knowledge on non-alcoholic fatty liver disease (NAFLD) and the hepatitis C virus (HCV)-associated liver fibrosis, and provides insight into the role of dysmetabolism in hepatic fibrogenesis. Clinical relevance of drugs correcting these metabolic disturbances in the reversion of liver fibrosis will also be discussed., Recent Findings: Liver fibrosis affects more than ten millions of people worldwide and may lead to cirrhosis, liver failure, and death. Recent epidemiological data indicate that the incidence of liver fibrosis is expected to triple during the next 10 to 15 years as a result of the HCV infection and NAFLD escalation. In accordance with the modern view of liver fibrogenesis, the pathways involved in the pathogenesis of hepatic fibrosis appear to be broadly similar regardless of the etiology., Summary: Some features of metabolic syndrome, including obesity, insulin resistance, and type 2 diabetes represent a strong risk factor in development and progression of hepatic fibrosis. However, whatever the cause, fibrosis culminates in cirrhosis and results in liver failure, thus, a potent anti-fibrotic therapy is urgently needed to reverse scarring and eliminate progression to cirrhosis.

Background: Liver fibrosis is a stage of non-alcoholic fatty liver disease (NAFLD) which is responsible for liver-related morbidity and mortality in adults. Accordingly, the search for non-invasive markers of liver fibrosis has been the subject of intensive efforts in adults with NAFLD. Here, we developed a simple algorithm for the prediction of liver fibrosis in children with NAFLD followed at a tertiary care center., Methods: The study included 136 male and 67 female children with NAFLD aged 3.3 to 18.0 years; 141 (69%) of them had fibrosis at liver biopsy. On the basis of biological plausibility, readily availability and evidence from adult studies, we evaluated the following potential predictors of liver fibrosis at bootstrapped stepwise logistic regression: gender, age, body mass index, waist circumference, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase, albumin, prothrombin time, glucose, insulin, triglycerides and cholesterol. A final model was developed using bootstrapped logistic regression with bias-correction. We used this model to develop the 'pediatric NAFLD fibrosis index' (PNFI), which varies between 0 and 10., Results: The final model was based on age, waist circumference and triglycerides and had a area under the receiver operating characteristic curve of 0.85 (95% bootstrapped confidence interval (CI) with bias correction 0.80 to 0.90) for the prediction of liver fibrosis. A PNFI >or= 9 (positive likelihood ratio = 28.6, 95% CI 4.0 to 201.0; positive predictive value = 98.5, 95% CI 91.8 to 100.0) could be used to rule in liver fibrosis without performing liver biopsy., Conclusion: PNFI may help clinicians to predict liver fibrosis in children with NAFLD, but external validation is needed before it can be employed for this purpose.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries, and its prevalence is increasing worldwide. It currently affects approximately 30% of adults and 10% of children and adolescents. The resulting increase in the number of patients with NAFLD is expected to translate into increased numbers of patients with liver cirrhosis, and hepatocellular carcinoma. In this context, it is particularly important to identify patients at risk for progressive chronic liver disease. Currently, liver biopsy is the gold standard to diagnose non-alcoholic steatohepatitis (NASH) and to establish the presence and stage of fibrosis. Due to the remarkable increase in the prevalence of NAFLD and the concomitant efforts in developing novel therapies for patients with NASH, non-invasive, simple, reproducible, and reliable non-invasive methodologies are needed. This paper provides a concise overview of the role of non-invasive diagnostic tools for the determination of presence and extent of fibrosis in NAFLD patients, with particular emphasis on the methods currently available in clinical practice.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in children and adolescents in industrialized countries. It is important to accurately determine the stage of fibrosis in these patients. The enhanced liver fibrosis (ELF) test has been validated for staging liver fibrosis in adult patients with chronic liver diseases, including NAFLD. We investigated the performance of this test in assessing liver fibrosis in children and adolescents with NAFLD, identified by biopsy., Methods: The ELF test was performed on a panel of serum samples collected from 112 consecutive subjects that were likely to have NAFLD (64 male, mean age of 13.8+/-3.3). A previously described and validated algorithm was used to analyze the data on hyaluronic acid (HA), amino-terminal propeptide of type III collagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels., Results: In pediatric patients with NAFLD, the ELF test predicted liver fibrosis stage with a high degree of sensitivity and specificity; results were superior to those reported for adults. The area under receiver operating characteristic curves/best possible ELF test cut-off values for the prediction of "any" (>or= stage 1), moderate-perisinusoidal (>or= stage 1b), moderate-portal/periportal (>or= stage 1c), significant (>or= stage 2), or advanced (>or= stage 3) fibrosis were 0.92/9.28, 0.92/9.33, 0.90/9.54, 0.98/10.18 and 0.99/10.51, respectively., Conclusions: The ELF test can be used to accurately assess the level of liver fibrosis in pediatric patients with NAFLD. This information is important for identifying patients with progressive fibrosis that require further histopathological analysis or therapeutic follow-up.

Unlabelled: Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in chronic liver disease patients. In this study, we assessed the value of TE for the prediction of fibrosis stage in a cohort of pediatric patients with nonalcoholic steatohepatitis. Furthermore, TE interobserver agreement was evaluated. TE was performed in 52 consecutive biopsy-proven nonalcoholic steatohepatitis patients (32 males, 20 females, age 13.6 +/- 2.44 years). The area under the receiver operating characteristic curves for the prediction of "any" (>or=1), significant (>or=2), or advanced fibrosis (>or=3) were 0.977, 0.992, and 1, respectively. Calculation of multilevel likelihood ratios showed that TE values <5, <7, and <9 kPa, suggest the presence of "any" fibrosis, significant fibrosis, and advanced fibrosis, respectively. TE values between 5 and 7 kPa predict a fibrosis stage of 1, but with some degree of uncertainty. TE values between 7 and 9 kPa predict fibrosis stages 1 or 2, but cannot discriminate between these two stages. TE values of at least 9 kPa are associated with the presence of advanced fibrosis. The intraclass correlation coefficient for absolute agreement was 0.961., Conclusion: TE is an accurate and reproducible methodology to identify pediatric subjects without fibrosis or significant fibrosis, or with advanced fibrosis. In patients in which likelihood ratios are not optimal to provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated.

Background & Aims: Although nonalcoholic fatty liver disease (NAFLD) is increasingly common, only a minority of affected individuals develop fibrotic liver disease. Based on its role in liver growth and repair, we explored whether Kruppel-like factor 6 (KLF6) plays a role in NAFLD progression., Methods: KLF6 expression in 31 fibrosis scored NAFLD liver biopsy specimens was assessed by real-time polymerase chain reaction. Transfected minigene constructs were used to study the effect of a polymorphism, KLF6-IVS1-27G>A, that promotes KLF6 alternative splicing in vitro. We genotyped KLF6-IVS1-27G>A in 3 groups of patients (UK group 1, n = 306; Italian group 2, n = 109; trio group 3, n = 61 children and parents)., Results: KLF6 expression was increased in association with increased steatosis, inflammation, and fibrosis in NAFLD livers. KLF6-IVS1-27G>A promoted alternative splicing of KLF6 and abrogated the up-regulation of both alpha-smooth muscle actin and collagen 1 in LX-2 cells. Group 1 genotyping identified KLF6-IVS1-27G>A in 44 of 306 (14.4%) patients. Notably, KLF6-IVS1-27G>A was associated significantly with milder NAFLD, with only 25% having more advanced fibrosis compared with 45% of wild-type (wt) individuals. This trend was confirmed in group 2. A linear regression analysis including all 415 patients, adjusted for age, sex, body mass index, and blood glucose level, confirmed that presence of the wt KLF6 allele was an independent predictor of fibrotic NAFLD. Furthermore, we have shown preferential transmission of the wt allele to children with fibrotic NAFLD., Conclusions: We report a functional polymorphism in the KLF6 gene associated with advanced NAFLD and believe further study of KLF6 may enhance our understanding of this disease process.

Aim: To identify the independent predictors of hepatic fibrosis in 69 children with nonalcoholic steatohepatitis (NASH) due to nonalcoholic fatty liver disease (NAFLD)., Methods: All patients with clinically suspected NASH underwent liver biopsy as a confirmatory test. The following clinical and biochemical variables at baseline were examined as likely predictors of fibrosis at histology: age, body mass index (BMI), systolic blood pressure (SBP), dyastolic blood pressure (DBP), fasting glucose, fasting insulin, homeostatic model assessment for insulin resistence (HOMA-IR), cholesterol, tryglicerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, gamma glutamil transferase (GT), platelet count, prothrombin time (PT)., Results: At histology 28 (40.6%) patients had no fibrosis and 41 (59.4%) had mild to bridging fibrosis. At multivariate analysis, BMI > 26.3 was the only independent predictor of fibrosis (OR = 5.85, 95% CI = 1.6-21)., Conclusion: BMI helps identify children with NASH who might have fibrotic deposition in the liver.

Objective: Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children., Design and Methods: In 72 biopsy-proven NAFLD children (aged 9-18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R; IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp); glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients., Results: Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 +/- 1.39 and 4.4 +/- 2. NASH was diagnosed in 38 and simple steatosis in 25 children; diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 41 patients. Median NAFLD activity (NAS) score was 3.42 +/- 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 +/- 6.3 in score 1 to 17.4 +/- 6.9 in score 2 (P = 0.01) and 22.2 +/- 6.8 ng/ml in score 3 (P < 0.001); FLI 2.56 +/- 1.40, 3.57 +/- 0.34, 4.45 +/- 0.64 respectively (P = 0.05)); ballooning (from 13.7 +/- 6.7 in score 1 to 17 +/- 7.5 in score 2 (P = 0.001) and 22.1 +/- 7.1 ng/ml in score 3 (P = 0.01); FLI 2.81 +/- 1.50, 3.40 +/- 1.65, 4.57 +/- 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 +/- 7 to18.3 +/- 6.9; P = 0.03; FLI 3.03 +/- 1.57 vs 3.92 +/- 077; P < 0.05) and NAS score (score 1-2: 12.9 +/- 6.9; score 3-4: 17 +/- 6.9 (P = 0.01); score 5-7: 22.9 +/- 7.5 ng/ml (P = 0.03); FLI 2.70 +/- 1.53, 3.12 +/- 1.53, 4.58 +/- 1.57 P = 0.01 and P = 0.05 between 1-2 vs 3-4 and 3-4 vs 5-7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r(0) = 0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r(0) = 0.4, P < 0.0001), steatosis (r(0) = 0.5, P < 0.0001) and NAS score (r(0) = 0.5, P < 0.0001)., Conclusions: Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.

Kabuki (Niikawa-Kuroki) syndrome (KS) is characterized by a distinctive face, mental retardation, growth deficiency, skeletal anomalies, dermatoglyphic abnormalities, palatal anomalies, congenital heart defects, and urogenital malformations. Congenital hepatic abnormalities have been sporadically described in patients with KS from the literature, consisting of extrahepatic biliary atresia, neonatal sclerosing cholangitis, and severe neonatal jaundice. We report here on an additional patient with a congenital abnormality of the liver consisting of hepatic fibrosis. To our knowledge, idiopathic congenital hepatic fibrosis has not been reported in KS. Thus, our observation expands the spectrum of liver malformations found in KS with the inclusion of hepatic fibrosis and supports the evidence that hepatic abnormalities may not be uncommon in KS. Clinician should be advised to search for the specific facial anomalies of KS in patients with syndromic congenital hepatic diseases, and KS should be added to the list of previously recognized multiple congenital anomaly syndromes with hepatic involvement. Due to the frequent association with congenital heart malformations, KS should be considered in the evaluation of patients with neonatal liver disease and cardiac malformation. Due to the expression patterns of Notch genes, involvement of the Notch signaling pathway in the development of heart and liver anomalies in KS should be considered., (Copyright 2003 Wiley-Liss, Inc.)

Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.